Intermolecular amidation of unactivated sp2 and sp3 C-H bonds via palladium-catalyzed cascade C-H activation/nitrene insertion

Article abstract of DOI:10.1021/ja062856v

This communication describes the Pd(OAc)₂-catalyzed intermolecular amidation reactions of unactivated sp² and sp³ C-H bonds using primary amides and potassium persulfate. The substrates containing a pendent oxime or pyridine group were amidated with excellent chemo- and regioselectivities. It is noteworthy that reactive C-X bonds were well-tolerated and a variety of primary amides can be effective nucleophiles for the Pd-catalyzed C-H amidation reactions. For the reaction of unactivated sp³ C-H bonds, β-amidation of 1° sp³ C-H bonds versus 2° C-H bonds is preferred. The catalytic reaction is initiated by chelation-assisted cyclopalladation involving C-H bond activation. Preliminary mechanistic study suggested that the persulfate oxidation of primary amides should generate reactive nitrene species, which then reacted with the cyclopalladated complex. Copyright

Full text of DOI:10.1021/ja062856v

Published on Web 06/27/2006
Intermolecular Amidation of Unactivated sp2 and sp3 C-H Bonds via
Palladium-Catalyzed Cascade C-H Activation/Nitrene Insertion
Hung-Yat Thu, Wing-Yiu Yu,*,† and Chi-Ming Che*
Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for
Drug DiscoVery and Synthesis, The UniVersity of Hong Kong, Pokfulam Road, Hong Kong
Received April 25, 2006; E-mail: cmche@hku.hk; bcwyyu@polyu.edu.hk
Scheme 1. Pd(II)-Catalyzed ortho-Amidation of 2-Arylpyridine
Transition metal-catalyzed C-N bond formation is of immense
interest due to the prevalence of amino groups in pharmaceuticals
and bioactive natural products.1 Notable achievements in catalytic
C-H bond amidation have been achieved by using Ru and Rh
catalysts with hypervalent iodine reagents and sulfonylamides.1e,2,3
According to the reports by Che,2 Dubois,3 and others,1c,e these
Table 1. Pd-Catalyzed ortho-Amidation of Aromatic Oximesa
catalytic systems involve reactive metal-imido/nitrene species,
which undergo insertion to C-H bonds. The reactivity for nitrene
C-H bond insertion follows the order of 3° > 2° . 1° bond,
paralleling the order of increasing C-H bond dissociation energies.2d
However, catalytic systems that can effect amidation of unactivated
aromatic and aliphatic 1° C-H bonds are sparse in the literature.2,3a,4
Recently, chelation directed/assisted transition-metal-catalyzed C-H
functionalization is receiving growing attention.5-7 We are attracted
to a seminal work by Sanford and co-workers,6 who showed that
oxime and pyridine groups can direct highly regio- and chemo-
selective Pd(II)-catalyzed â-acetoxylation of sp2 and sp3 C-H bonds
with PhI(OAc)2 as a stoichiometric oxidant. We envisioned that
cascade C-H bond activation via Pd(OAc)2-mediated cyclometa-
lation followed by nitrene insertion reactions could be a plausible
approach for selective amidation of 1° or 2° C-H bonds. Prior to
this study, we observed that Pd(II) complexes, such as palladium
carboxylates and [Pd(TTP)] [H2TTP ) tetrakis(p-tolyl)porphyrin],
can catalyze intramolecular nitrene C-H insertion,2,3 which may
occur via reactive Pd(II)-nitrene species. During the course of this
study, Buchwald and co-workers described a related Pd-catalyzed
cyclization of 2-acetaminobiphenyl to N-acetyl carbazole.1b
Our investigation began by examining the intermolecular ami-
dation reaction of 2-phenylpyridine (Scheme 1). A series of
catalysts, oxidants, and nitrene sources were screened (see Sup-
porting Information). Thus, under the optimized conditions [Pd-
(OAc)2 (5 mol %), trifluoroacetamide (A2, 1.2 equiv), K2S2O8 (5
a Conditions: 1 equiv of substrate, 1.2 equiv of A1/A2, 5 mol % of
equiv), MgO (2 equiv), DCE, 80 °C, 7 h], the ortho-amidated
product, N-(2-pyridylphenyl)-2,2,2-trifluoroacetamide, was obtained
in 92% isolated yield. The molecular structure of N-(5-methyl-2-
Pd(OAc)2, 5 equiv of K2S2O8 in DCE, 80 °C, 14-20 h. b Isolated yield.
Scheme 2. Effect of Amides on Amidation of 1b
pyridylphenyl)-2,2,2-trifluoroacetamide has been established by
X-ray crystallography (Supporting Information). It is noteworthy
that this protocol was conducted without the need for air-/moisture-
proof conditions.
Apart from 2-arylpyridines, O-methyl oximes were examined
for the Pd-catalyzed amidation reaction, and the results are listed
in Table 1. O-Methyl oximes derived from benzaldehyde, acetophe-
none, and para-substituted benzaldehydes were effectively con-
verted to their corresponding anilides by regioselective ortho-C-H
amidation (entries 1-5). Notably, the C-I bond is well tolerated
in our Pd-catalyzed protocol; chemo- and regioselective ortho-
amidation of 4-iodoacetophenone O-methyl oxime (1c) was achieved
in 87% yield (entry 3). When oxime derived from 3-bromobenzyl-
aldehyde (1g) was employed as substrate, the 2,4-regioisomer 1g-
A1 was obtained exclusively in 92% yield (entry 7). The analogous
catalytic ortho-amidation reactions of sterically hindered oximes
were found to be sluggish. For example, when 3,5-dimethoxybenzyl-
aldehyde O-methyl oxime was employed as substrate, <10%
conversion was registered based on 1H NMR analysis of the crude
mixture.
As shown in Scheme 2, 1° amides, including carbamates,
acetamides, and sulfonamides, are effective nucleophiles for the
Pd-catalyzed ortho-amidation of 1b. Interestingly, amides bearing
a CdC bond, such as cinnamide (A6), can be employed for the
† Current address: Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hunghom, Kowloon, Hong Kong.
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10.1021/ja062856v CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Pd-Catalyzed ortho-Amidation of Aliphatic Oximesa
in the catalytic intramolecular nitrene C-H bond insertion reaction;
(2) some Pd(IV) complexes have been characterized from reactions
involving strong oxidants;6b,10 and (3) examples of Pd imido11a and
Pd nitrene11b,c complexes are known in the literature.
We also noted that treatment of 3 with excess of PhIdNSO2-
(p-Cl-C6H4) or stoichiometric PhIdNSO2(p-Cl-C6H4) and 1 mol
% of [Ru(TTP)(CO)] gave a yellow complex. This complex has
the “3 + [NSO2(p-Cl-C6H4)]” formulation based on ESI-MS
analysis.9 Treating this yellow complex with HCl afforded the
corresponding monoamidated product of 2-phenylpyridine in 85%
yield (based on the amount of 3 employed).
In conclusion, a catalytic alkane amidation protocol based on
cascade chelation-directed cyclopalladation/amidation reactions was
developed. This protocol enables intermolecular amidation of
unactivated sp2 and sp3 C-H bonds with remarkable regio- and
chemoselectivities. Further investigation on the scope and the
mechanism of the reaction is in progress.
a Conditions: 1 equiv of substrate, 1.2 equiv of A2/A5, 5 mol % of Pd-
(OAc)2, 5 equiv of K2S2O8 in DCE, 80 °C, 14-20 h. b Isolated yield. c Ob-
tained as an E/Z mixture. d Yield based on 77% conversion. e See ref 8.
Scheme 3. Mechanistic Proposal for the Amidation Reaction
Acknowledgment. This work is supported by the Areas of
Excellence Scheme (AoE/P-10/01) established under the University
Grants Council (HKSAR), the University Development Fund
(HKU), and the Hong Kong Research Grants Council (HKU7026-
03P).
Scheme 4. Conversion of Benzamide to Methyl
N-(2-Methoxyphenyl)carbamate
Supporting Information Available: Experimental details and
spectroscopic and analytical data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
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formed in 68% yield. However, benzamide, 2° amides (e.g.,
pyrrolidinone, succinimide, N-methylformamide) and 1°/2° amines
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1b, and the substrate was recovered quantitatively.
Importantly, catalytic amidation of unactivated sp3 C-H bonds
has also been achieved (Table 2). Employing the following
protocol: [Pd(OAc)2 (5 mol %), sulfonamide A5 (1.2 equiv),
K2S2O8 (5 equiv), DCE, 80 °C], aliphatic O-methyl oximes (2a-
d) would undergo regioselective â-amidation of a 1° sp3 C-H bond
to give the corresponding monoamidated product in 76-88% yield
(entries 1-4). Amidation at the 2° sp3 C-H bond was not observed.
No diamidation product was obtained even employing excess
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amidation reaction is initiated by chelation-directed cyclopalladation
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+
K2S2O8” protocol in the presence of methanol (3 equiv), and methyl
N-(2-methoxyphenyl)carbamate was obtained in 55% yield without
formation of any amidation product (Scheme 4).9 The carbamate
formation is best accounted for by a nitrene intermediate which
underwent Curtius rearrangement to isocyanate. Nucleophilic attack
of the isocyanate by methanol gave methyl N-phenylcarbamate, and
subsequent C-H activation/ortho-methoxylation gave methyl N-(2-
methoxyphenyl)carbamate as the product.
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uncertain: metal-free (Scheme 3, path A) versus metal-bound
(Scheme 3, path B) nitrene. Reactive Pd(II)-nitrene species
(alternative formulation of a Pd(IV)-imido species cannot be
excluded) is evidenced by the following: (1) analogy of the
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